Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome

Abstract

Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.

Senescence of alveolar stem cells drives progressive pulmonary fibrosis

“…Pathways upregulated pathways in Sin3a-LOF AT2 cells compared to wildtype AT2 cells included oxidative phosphorylation, mitochondrial dysfunction, sirtuin signaling, EIF2 signaling, and mTOR signaling, which were all identified in our bulk AT2 cell RNA-seq analyses. In addition, our scRNA-Seq data revealed differential expression of several other genes and pathways linked to cellular senescence, including eIF4 and p70S6K (46), protein ubiquitination (56,57), PI3K/AKT signaling (21)(22)(23)(24), phagosome maturation (58,59), VEGF signaling (60), integrin signaling (61), NRF2mediated oxidative stress (62)(63)(64)(65), actin nucleation (66), and MAPK signaling (67-69) ( Fig 2H).…”

Reprogramming of human fibroblasts into osteoblasts by insulin-like growth factor-binding protein 7

“…Cellular senescence is regarded as detrimental for tissue repair and regeneration since it induces replicative aging in cells, which directly contributes to their loss of regenerative capacity in tissue repair . Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner . Thus, induction of cell senescence in the reprograming of fibroblast into OB appears contradictory.…”

“…[43][44][45][46] Additionally, SASP proteins released by senescent cells can disrupt tissue homeostasis and potentially act on neighboring cells in a paracrine signaling manner. 45,[47][48][49] Thus, induction of cell senescence in the reprograming of fibroblast into OB appears contradictory. Nevertheless, emerging evidence in embryonic and adult tissues indicates that cell senescence is beneficial in tissue homeostasis.…”

Epigenetic treatment of dermatologic disorders

“…Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults. Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV‐radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen species (Dinkova‐Kostova et al, ; Dodson et al, ; Hiebert et al, ; Jadkauskaite et al, ; Raghunath et al, ; Siegenthaler et al, ; Sivandzade, Prasad, Bhalerao, & Cucullo, ; Tonelli, Chio, & Tuveson, ; Vega, Krajisnik, Zhang, & Wondrak, ; Yamamoto, Kensler, & Motohashi, ).…”

“…muscular system, and internal organs, cells in every tissue type, including skin, require a continuous and adequate supply of mitochondrial energy for their survival and proper function(Baeeri et al, 2019;Dinkova-Kostova, Kostov, & Kazantsev, 2018;Joshi & Mochly-Rosen, 2018;Martinelli et al, 2017;Naidoo, Hanna, & Birch-Machin, 2018; Wlaschek, Singh, Sindrilaru, Crisan, & Scharffetter-Kochanek, 2019;Zhou et al, 2018). Representing the outermost surface of the body, skin is uniquely vulnerable to a plethora of environmental insults.Exposure to harmful chemicals, xenobiotics, oxidative stress, and solar UV-radiation is mitigated by various protective mechanisms that rely on signaling networks and the expression of proteins involved in the detoxification of compounds or reactive oxygen speciesDodson et al, 2019;Hiebert et al, 2018;Jadkauskaite et al, 2017;Raghunath et al, 2018;Siegenthaler et al, 2018;Sivandzade, Prasad, Bhalerao, & Cucullo, 2019;Tonelli, Chio, & Tuveson, 2018;Vega, Krajisnik, Zhang, & Wondrak, 2017;Yamamoto, Kensler, & Motohashi, 2018).…”